(093) Late-Onset Tay-Sachs (LOTS) Disease Presenting with Psychosis and Cerebellar Atrophy: A Model Case Describing an Integrated Approach to Rare Diseases with Neuropsychiatric Manifestations

Abstract: Background/Significance: Late-onset Tay-Sachs (LOTS) disease is a rare Hexosaminidase A (HEXA) disorder which typically presents with progressive neurologic and psychiatric manifestations in teens and young adults (Toro, 2020). However, variability in symptoms often leads to missed or delayed diagnoses (Lopshire, 2023). We describe the presentation, diagnostic evaluation, and treatment of a 22-year-old male with no prior medical or psychiatric history who had laboratory testing diagnostic of LOTS. 



Case: The patient presented with six months of impulsivity and psychotic symptoms, including delusions, auditory hallucinations, disorganized speech and behaviors, paranoia, and responding to internal stimuli. Throughout four successive hospitalizations spanning a total of 59 days, psychiatric evaluation demonstrated the aforementioned symptoms, and physical examination revealed moderate hypokinetic dysarthria. Extensive metabolic, infectious, and inflammatory testing failed to identify a cause for these symptoms, but brain MRI demonstrated isolated cerebellar atrophy. Treatment focused on several presumed diagnoses, including autoimmune encephalitis, without sustained improvement in symptoms. Notably, his neurologic status worsened significantly while taking risperidone. 

Given persistent lack of improvement with usual treatment, abnormal MRI findings, and observed neurological symptoms, ultra-rapid whole genome sequencing was performed during a fifth hospitalization and revealed a paternally inherited pathogenic variant in the HEXA gene and a maternally inherited variant of uncertain significance. Further testing revealed a low HEXA activity level, confirming the LOTS diagnosis. Concomitantly, psychiatric management with aripiprazole and lorazepam was optimized to treat psychotic symptoms and facilitate outpatient management. 



Discussion: This case highlights several key clinical lessons for C-L psychiatrists, the first of which is the need to consider rare genetic diseases in the differential diagnosis when patients present with new-onset neurologic and psychiatric symptoms (Coker, 1991). Second, it emphasizes the importance of assessing response to treatment, including failure to respond to first-line treatments, as part of the diagnostic process. Third, the case exemplifies the integration of subspecialty expertise into the evaluation of patients with atypical imaging results. Finally, it illustrates the benefits of timely access to whole genome sequencing for patients with rare diseases (Souche, 2022).

Conclusion/Implications: This case describes the clinical evaluation and treatment of a patient with LOTS who presented with psychotic symptoms, dysarthria, and a brain MRI demonstrating cerebellar atrophy. It also draws attention to the diagnostic strategies, laboratory testing methods, and interdisciplinary approaches that can be utilized when a patient presents with psychiatric symptoms in the setting of otherwise unexplained physical examination and neuroimaging findings. 



References:

Coker SB. The diagnosis of childhood neurodegenerative disorders presenting as dementia in adults. Neurology. 1991;41(6):794-798. 

Lopshire MC, Tifft C, Burns J, et al. The diagnostic journey for patients with late-onset GM2 Gangliosidoses. Mol Genet Metab Rep. 2023;37:101014. 

Souche E, Beltran S, Brosens E, et al. Recommendations for whole genome sequencing in diagnostics for rare diseases. Eur J Hum Genet. 2022;30(9):1017-1021. 

Toro C, Shirvan L, Tifft C. HEXA Disorders. In: Adam MP, Feldman J, Mirzaa GM, et al., eds. GeneReviews. Seattle (WA): University of Washington, Seattle; October 1, 2020.

Presentation Eligibility: This case was presented as a poster at Rare Disease Day 2024 at the NIH. If accepted, the case could be presented to a broader audience of C-L psychiatrists and trainees. The poster has been updated to include additional references reviewing the use of whole genome sequencing in psychiatric assessment.

Diversity, Equity, and Inclusion: This case report describes the diagnostic evaluation and treatment of late-onset Tay-Sachs disease, which is classified as a rare disease by the National Organization for Rare Disorders. Patients with rare diseases are often marginalized by the health care system, may experience lengthy and costly treatment courses before finding a definitive diagnosis, and frequently face significant financial and geographical barriers to enrolling in applicable clinical trials. Regarding authorship, the individuals who contributed to this submission include three psychiatry residents, one junior faculty member, and two senior faculty members. Two of these authors are first-generation physicians.